Memory CD8 T cells serve as excellent sentinels of the adaptive immune system and play a prominent role in conferring immunological protection against intracellular pathogens as well as tumorigenic cells. The generation and maintenance of a functionally competent memory CD8 T cell compartment is influenced by multiple factors, including the inducing antigen, the degree of stimulation, and the presence of accessory cells. Our laboratory, as well as others, has documented that CD4 T cells are vital for the generation and maintenance of pools of functionally competent memory CD8 T cells that are optimally configured for protective purposes. It remains unclear, however, which subsets and specificities of CD4 T cells promote the differentiation, maintenance, and protective potential of memory CD8 T cells. Moreover, it is not known whether all constituents of heterogeneous memory CD8 T cell pools are equally dependent upon CD4 T cell help. The objective of the proposed studies is to provide new information regarding the requirements of CD4 T cell help for the establishment of memory CD8 T cell responses, the long term maintenance of memory T cell numbers and functional potential, and the ability of memory CD8 T cells to mount protective secondary responses. We hypothesize that CD4 T cells promote the generation of memory CD8 T cell precursors during the induction phase of the response and that, subsequently, CD4 T cells support the stable maintenance of functionally competent memory CD8 T cells that are capable of participating in recall responses. To address this we propose: (1). To determine whether distinct CD8 T cell subsets require CD4 T cell help to transition into memory T cells. (2). To define the requirements for distinct CD4 T cell subsets for the generation and maintenance of memory CD8 T cells. (3). To determine the impact of CD4 T cells during secondary CD8 T cell responses. A key issue for infection control and vaccine design is determining how to configure and sustain long-lived pools of memory T cells that are most effective at clearing pathogens following secondary exposures. Defining the interplay between CD4 and CD8 T cells that is necessary for the formation, function, and persistence of memory CD8 T cells is, therefore, of both fundamental and clinical relevance. Ultimately the information provided by these studies may form the foundation for translational initiatives designed to enhance vaccine-mediated protective immunity as well as boost responses that are inferior due to underlying defects in CD4 helper T cell responses.